Genetic testing offers the opportunity to identify sources of inter-individual variability in drug disposition and response, with the goal of individualizing therapy (drug selection and dose) and improving patient and public health outcomes. A small number of pharmacogenetic tests are already in clinical use, and other promising examples are emerging, including tests to improve the safety of warfarin, tamoxifen and tacrolimus therapy. Despite this promise, most studies have been undertaken in resource-intensive, tertiary care centers and their relevance for rural health care practice is unknown. Information gaps are especially notable for Alaska Native and American Indian (AI/AN) communities living in rural locations;addressing these gaps requires attention to scientific, health service and cultural issues. We lack knowledge about relevant genetic and environmental variation within indigenous populations of the US, limiting our ability to inform the design and implementation of pharmacogenetic testing services for these groups. In addition, little is known about potential cultural barriers to genetic research within indigenous communities that might delay this research agenda or limit receptiveness to pharmacogenetics, or about the resources that would be needed for optimal implementation of this clinical approach. With these uncertainties and knowledge gaps in mind, we propose to create a new Center on Pharmacogenetics in Rural and Underserved Populations. This Center will work in partnership with indigenous communities in Anchorage and the Yukon-Kuskowkim delta in Alaska and in northwestern Montana, and with rural providers in these locations and in rural Washington, to ensure that there is adequate community understanding, biological knowledge, and medical infrastructure to respond appropriately to national recommendations or mandates related to pharmacogenetics. Our Center will utilize community-based participatory research methods to evaluate community and clinical perspectives on pharmacogenetics;pursue foundational research in AI/AN and rural communities related to genetic variation and response to warfarin, tamoxifen and tacrolimus therapy;evaluate gene-environment interactions related to coagulation factors in one indigenous community;and lay the groundwork for a research infrastructure linking AI/AN communities rural practices to pharmacogenetics researchers. RELEVANCE: Completion of the specific aims proposed in this multi-disciplinary, multi-cultural grant application could improve our understanding of pharmacogenetic variability and enhance drug safety/efficacy in American Indian and Alaska Native peoples, by addressing major scientific knowledge gaps and potential cultural/structural barriers to pharmacogenetic research and its clinical testing.